FeCl₃ -Mediated Carbenium Ion-Induced Intramolecular Cyclization of N -Tethered Alkyne-Benzyl Alkanols

Devi N.R., Behera B.K., Saikia A.K.

Indium(III) chloride can be efficiently used for the synthesis of 4-vinylpyrrolidine from N-tethered alkyne-alkenol in good yields. The reaction is highly stereo- and regioselective.

Borthakur U., Borah M., Deka M.J., Saikia A.K.

A convenient protocol has been established for the synthesis of 1-tosyl-2,3,4,5-tetrahydro-1H-indeno[1,2-b]pyridine via cascade cyclization and Friedel-Crafts reaction of 4-methyl-N-(pent-4-yn-1-yl)benzenesulfonamides and aldehydes in good yields. The methodology has been used for the total synthesis of the antidepressant agent (±)-5-phenyl-2,3,4,4a,5,9b-hexahydro-1H-indeno[1,2-b]pyridine.

Saikia A.K., Indukuri K., Das J.

A diastereoselective protocol has been established for the synthesis of 4-O-tosyl piperidine containing hexahydroindolizin-3(2H)-one, hexahydro-1H-quinolizin-4(6H)-one and 1,3,4,10b-tetrahydropyrido[2,1-a]isoindol-6(2H)-one derivatives via the aza-Prins cyclization reaction of cyclic N-acyliminium ions mediated by p-toluene sulphonic acid (p-TSA) under mild conditions. The reaction is highly diastereoselective and gives excellent yields. This method has been applied to an efficient total synthesis of indolizidine alkaloids, (±)-epi-indolizidine 167B and 209D.

Ghosh P., Saha P., Bondalapati S., Indukuri K., Saikia A.K.

Intramolecular C-C bond formation of oxygen- and nitrogen-tethered alkynes and epoxide mediated by Lewis acid under ambient conditions is described. A simple procedure for the synthesis of 3,6- and 5,6-dihydropyrans and 3,4-dehydropiperidines from acyclic building blocks in good yields without using any transition metal is shown.

Ramachandran P.V., Mitsuhashi W., Nicponski D.R.

A novel and synthetically facile production of 2-substituted pyrrolidines from commercially available nitriles is reported herein. This methodology is operationally simple, and only requires the use of an extraction and a single chromatographic purification to furnish the title compounds in high purity and very good yields.

Vincent G., Karila D., Khalil G., Sancibrao P., Gori D., Kouklovsky C.

Running rings! Stereodivergent access to piperidine alkaloids by ring-rearrangement metathesis of N-acylated nitroso Diels–Alder cycloadducts followed by reductive alkylation is described. This methodology is illustrated by the formal synthesis of porantheridine and the total synthesis of andrachcinidine (see scheme). The approach also brings further insights into the configurational stability of nitroso Diels–Alder cycloadducts.

Lorthiois E., Breitenstein W., Cumin F., Ehrhardt C., Francotte E., Jacoby E., Ostermann N., Sellner H., Kosaka T., Webb R.L., Rigel D.F., Hassiepen U., Richert P., Wagner T., Maibaum J.

The small-molecule trans-3,4-disubstituted pyrrolidine 6 was identified from in silico three-dimensional (3D) pharmacophore searches based on known X-ray structures of renin-inhibitor complexes and demonstrated to be a weakly active inhibitor of the human enzyme. The unexpected binding mode of the more potent enantiomer (3S,4S)-6a in an extended conformation spanning the nonprime and S1' pockets of the recombinant human (rh)-renin active site was elucidated by X-ray crystallography. Initial structure-activity relationship work focused on modifications of the hydrophobic diphenylamine portion positioned in S1 and extending toward the S2 pocket. Replacement with an optimized P3-P1 pharmacophore interacting to the nonsubstrate S3(sp) cavity eventually resulted in significantly improved in vitro potency and selectivity. The prototype analogue (3S,4S)-12a of this new class of direct renin inhibitors exerted blood pressure lowering effects in a hypertensive double-transgenic rat model after oral administration.

Yeh M.P., Liang C., Fan C., Chiu W., Lo J.

The FeCl(3)-promoted synthesis of 2-azaspiro[4.6]undec-7-ene rings proceeds via ring expansion/cyclization/chlorination of N-tosyl-N-(3-arylpropargyl)-tethered 6-methylbicyclo[4.1.0]heptan-2-ols. This azaspirocyclic ring skeleton can also be obtained in one pot from the tert-butyldimethylsilyl-protected N-tosyl-N-(3-arylpropargyl)-tethered 3-methylcyclohex-2-en-1-ols and diethylzinc/diiodomethane.

Yeh M.P., Fang C., Lin H.

A simple and efficient FeCl3-promoted cyclization/chlorination of cyclic tosylamine-tethered 8-aryl-2-en-7-yn-1-ols was observed. The reaction proceeded instantaneously at 23 °C in air to afford (Z)-4-(arylchloromethylene)-substituted azaspirocycles in good to excellent yields. This transformation can also be applied to the synthesis of spirocarbocyclic analogues from cyclic 8-aryl-2-en-7-yn-1-ols and FeCl3.

Emer E., Sinisi R., Capdevila M.G., Petruzziello D., De Vincentiis F., Cozzi P.G.

Gray D., Davoren J., Harris A., Nason D., Xu W.

Herein we would like to communicate that an unstabilized azomethine ylide generated from commercial trimethylamine N-oxide will undergo a remarkable 1,3-dipolar cycloaddition in good yield with electron-rich and unpolarized olefins. A broad range of substituents on the alkenes are tolerated provided they are compatible with excess LDA. This demonstration of novel reaction scope should encourage others to try trimethylamine N-oxide as an azomethine ylide precursor in the synthesis of challenging 3,4-disubstituted pyrrolidines.

Yadav J.S., Reddy B.V., Ramesh K., Kumar G.G., Grée R.

The reaction of aldehydes with N-tosyl homoallylamine in the presence of a solution of tetrafluoroboric acid-diethyl ether complex in dichloromethane at ambient temperature gave the 4-fluoropiperidines in good yields and with high cis-selectivity. This aza-Prins-type cyclization has a wide scope and the use of HBF4·OEt2 makes this procedure simple, convenient, and cost-effective for the preparation of 4-fluoropiperidines.

Biswas S., Maiti S., Jana U.

A novel, simple, and straightforward one-pot reaction of alkynes with various alcohols in the presence of iron salts (FeCl3 and FeBr3) was described to yield the corresponding alkenyl halides with complete regioselectivity and highstereoselectivity. The reaction is high yielding and works under mild conditions. The iron salts act as Lewis acids and a source of halides. The reaction tolerates a wide variety of functional groups. Noteworthy is that this method is cheap, efficient, and environmentally friendly.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Liu Z., Wang J., Han J., Zhao Y., Zhou B.

This work demonstrated an efficient and mild method for preparing various substituted alkenyl halides via direct C–C bond formation of benzyl alcohols and aryl alkynes in CH 2 Cl 2 at 50 °C by using 50 mol % of FeCl 3 ·6H 2 O or FeBr 3 . Compared with the systems using excessive boron trihalides and stoichiometric n -BuLi to prepare substituted alkenyl halides, the present procedure would provide an excellent alternative due to the environmentally benign system and atom efficiency. This work demonstrated an efficient and mild method for preparing various substituted alkenyl halides via direct C–C bond formation of benzyl alcohols and aryl alkynes in CH 2 Cl 2 at 50 °C by using 50 mol % of FeCl 3 ·6H 2 O or FeBr 3 . Compared with the systems using excessive boron trihalides and stoichiometric n -BuLi to prepare substituted alkenyl halides, the present procedure would provide an excellent alternative due to the environmentally benign system and atom efficiency.

Sherry B.D., Fürstner A.

Transition metal catalysts, particularly those derived from the group VIII-X metals, display remarkable efficiency for the formation of carbon-carbon and carbon-heteroatom bonds through the reactions of suitable nucleophiles with organic electrophilic partners. Within this subset of the periodic table, palladium and nickel complexes offer the broadest utility, while additionally providing the deepest mechanistic insight into thus-termed "cross-coupling reactions". The mammoth effort devoted to palladium and nickel catalysts over the past 30 years has somewhat obscured reports of alternative metal complexes in this arena. As cross-coupling reactions have evolved into a critical support for modern synthetic chemistry, the search for alternative catalysts has been taken up with renewed vigor.When the current generation of synthetic chemists reflects back to the origins of cross coupling for inspiration, the well-documented effect of iron salts on the reactivity of Grignard reagents with organic electrophiles surfaces as a fertile ground for alternative catalyst development. Iron possesses the practical benefits more befitting an alkali or alkaline earth metal, while displaying the unique reactivity of a d-block element. Therefore the search for broadly applicable iron catalysts for cross coupling is an increasingly important goal in modern synthetic organic chemistry.This Account describes the evolution of iron-catalyzed cross coupling from its inception in the work of Kochi to the present. Specific emphasis is placed on reactivity and synthetic applications, with selected examples from acyl-, alkenyl-, aryl-, and alkyl halide/pseudohalide cross coupling included. The typical reaction partners are Grignard reagents, though organomanganese, -copper, and -zinc derivatives have also been used in certain cases. Such iron-catalyzed processes occur very rapidly even at low temperature and therefore are distinguished by broad functional group compatibility. Furthermore, recent advances in carbon-heteroatom bond formation and studies relevant to the general reactivity of in situ generated and structurally defined "low-valent" iron catalysts are presented.The preparative aspects of iron-catalyzed cross coupling are encouraging, but the inclination to classify these processes within the characteristic reaction manifold is premature, as mechanistic studies have evolved at a comparatively slow pace. A typical protocol for cross coupling employs an Fe(+2) or Fe(+3) precatalyst, which is reduced in situ by the organometallic nucleophile. The nature of the resulting active component(s) is still best described, more than 30 years later, in Kochi's original terms as a "reduced form of soluble iron". Despite huge gaps in our current knowledge, three distinct mechanisms have been formulated, largely based on empirical evidence: a "canonical" cross-coupling process, a manifold wherein alkylation of an organoiron intermediate replaces transmetalation as a key step, and finally a proposal reliant on the formation of nucleophilic ate complexes. Conjecture and speculation abound, but precisely what constitutes the catalytic cycle in iron-catalyzed cross coupling remains an extremely challenging unanswered question.

Jaiswal G., Pan S.C.

AbstractFerric chloride mediated dearomative spirocyclization of biaryl ynones for the synthesis of new series of densely functionalized 3,3‐spiroindanone derivatives has been reported. This study is the first to describe the regioselective synthesis of a five‐membered ring from biaryl ynones. The scope of the reaction is broad and the spirocyclic products were obtained in moderate to good yields (up to 87 %) and with high stereoselectivities.

Cruz D.A., Sinka V., Padrón J.I.

A review of the last 10 years of diastereoselective halogenation methods is presented. They have been divided by reactions into alkenes, alkynes, and heterocycles. In many of the cases, the use of transition metals is described. In all of them, the mechanistic approach proposed by the authors and justifying the obtained diastereoselection is discussed. A miscellaneous section is also included in which allylic fluorinations, double bond isomerizations, ring expansion, and ring-opening halogenations are discussed.

Frolov N.A., Vereshchagin A.N.

Piperidines are among the most important synthetic fragments for designing drugs and play a significant role in the pharmaceutical industry. Their derivatives are present in more than twenty classes of pharmaceuticals, as well as alkaloids. The current review summarizes recent scientific literature on intra- and intermolecular reactions leading to the formation of various piperidine derivatives: substituted piperidines, spiropiperidines, condensed piperidines, and piperidinones. Moreover, the pharmaceutical applications of synthetic and natural piperidines were covered, as well as the latest scientific advances in the discovery and biological evaluation of potential drugs containing piperidine moiety. This review is designed to help both novice researchers taking their first steps in this field and experienced scientists looking for suitable substrates for the synthesis of biologically active piperidines.

Khan S., Baire B.

In this review, we discussed about the synthetic developments in the field of Fe-catalysis for the formation of - bonds through the coupling of alkynes and alcohols, for the period of 13 years (2008-2020). These strategies fulfil important Green Chemistry principles, as they are highly atom economic (up to 100 %), no toxic by-products (only water), employs highly abundant and low toxic alcohols (no need for any pre-functionalization hence step economy) and cheaper Fe-catalysts. Having these advantages, one can predict that in the coming years a large number of fascinating new iron-catalyzed reactions will be developed for the organic synthesis. We hope that this review article will be highly useful for the synthetic community to design and develop new Fe-catalyzed coupling reactions and keeps the content in the right prospect.

Chanda R., Kar A., Das A., Chakraborty B., Jana U.

An Fe(OTf)3-catalysed carboarylation of alkynes is reported for the straightforward synthesis of densely substituted 1,2-dihydroquinolines from N-propargyl anilides and π-activated alcohols. The reaction provides a new method for the synthesis of highly substituted benzofused six-membered heterocycles by the formation of two carbon-carbon bonds and one ring in a single step. The power of the methodology was further extended to the synthesis of substituted chromene and thiochromene derivatives in high yields. In addition, substituted quinoline derivatives were also achieved in a single step in the presence of FeCl3 through detosylation/aromatisation. A number of control experiments have been performed and a plausible mechanism has also been proposed to explain the formation of the products.

Sahu A.K., Unnava R., Behera B.K., Saikia A.K.

A simple methodology for the regioselective synthesis of substituted dibenzocyclohepta[1,2-a]naphthalenes from phenylacetaldehydes and ortho-alkynyl benzyl alcohols in the presence of a Lewis acid has been developed.

Saikia A.K., Devi N.R., Shit S., Behera B.K.

An intramolecular Friedel–Crafts cyclization reaction catalyzed by indium(III) chloride for the formation of 4-vinyl-1,2,3,4-tetrahydroisoquinoline from N-tethered benzyl-alkenol in good yields has been described. The reaction is highly regioselective and generates an exocyclic vinyl functionality in the piperidine ring. The reaction is compatible with a wide range of functional groups. The strategy is demonstrated for the formal synthesis of (±)-isocyclocelabenzine alkaloid.

Smolobochkin A.V., Gazizov A.S.

The review summarizes methods of synthesis of 3-arylidenepyrrolidines, illustrated by the most typical examples, published in 2017–2019. The methods are divided into three main groups: modification of the 1-pyrroline (pyrrolidine) ring, intramolecular and intermolecular cyclization of unsaturated acyclic precursors.

Hong Y., Santhoshkumar R., Cheng C.